Diffuse large B-cell lymphoma (DLBCL) is one of the most common subtypes of non-Hodgkin lymphoma. It is a heterogeneous disease, and a distinctive subgroup of patients with different treatment outcome can be identified based on clinical and molecular prognostic factors. Cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy has been the standard systemic therapy for this disease with a cure rate of 40% to 50%, although, more recently, the addition of rituximab has been shown in phase III trials to confer a significant survival benefit in both older and younger patients. To further improve on the treatment outcome of this disease, dose-dense, and/or dose-intense regimens have been developed and tested against CHOP. However, these regimens are not yet accepted as standard therapy because of the increased toxicity as well as the uncertain benefit over CHOP with rituximab. In patients with localized DLBCL, available randomized trials suggest that radiation therapy improves local control and disease-free survival and that the addition of radiation therapy cannot replace inadequate chemotherapy.